Xeroderma pigmentosum complementation group C (XPC) is the key recognition factor of DNA damage in global genome nucleotide excision repair. Complete loss of XPC function results in a disease known as Xeroderma pigmentosum. Although XP represents an extreme defect in the function of the XPC protein, subtle variation in the function of this protein occurs in the general population due to inheritance of single nucleotide polymorphisms (SNPs) which are implicated in some inherited cancer susceptibilities. To date, over 90 SNPs in the XPC gene have been reported an analysis of the effect of these on disease risk, or evaluation of individual phenotypic effects, is impractical. However, it is known that genetic variation in human populations is not arrayed as independent SNPs but as various combinations of SNPs (haplotypes). Therefore, the phenotypic effects of haplotypes, rather than SNPs, should be examined to determine the role of genetic variability in disease risk. To our knowledge, neither a comprehensive haplotype analysis of the entire XPC genomic sequence nor an evaluation of the functional effects of the XPC haplotypes has been conducted. I plan to address these gaps in knowledge by testing my genotype/phenotype hypothesis, specifically that certain XPC haplotypes adversely modify transcriptional processes and/or protein integrity, and consequently exhibit impairments in DNA repair capacity which causes higher levels of persisting genetic damage. I used bioinformatics to and conducted a comprehensive haplotype analysis of the entire genomic sequence of XPC and characterize the effect of haplotypes on genetic damage in a population of smokers that I used as a model of an environmentally exposed population. To test this hypothesis the following Specific Aims are proposed: Aim 1: To determine biological effects of XPC haplotypes on DNA repair capacity (DRC) and genetic damage (specifically, genotype/phenotype relationships). Aim 2: To characterize functional significance of XPC haplotypes by defining effects of XPC haplotypes on transcription and protein expression. PUBLIC HEALTH RELEVANCE: This study will comprehensively examine the biological significance and the functional impact of genetic variants, in the context of haplotypes, of a key DNA repair gene. The multidisciplinary approach of this fellowship project will combine bioinformatics, molecular biology, and toxicology in order to obtain new mechanistic information on how adverse XPC haplotypes influence susceptibility genetic damage by environmental insult is linked to disease, as the biological effects of these haplotypes on DNA damage response and DNA repair capacity have not been previously evaluated. An obvious future direction is to transfer this genomic insight into public health precautions.